Abstract Although CD8+ T cells face intense immunosuppressive and metabolic pressures within the tumor microenvironment (TME), a subset of these cells can mount resilient responses to immune checkpoint inhibitor (ICI) therapy. We recently identified a population of such resilient CD8+ T cells in patients with advanced solid tumors who were unresponsive to standard-of-care cancer therapies but showed clinical benefit from ICI or combination ICI therapy. Among these resilient CD8+ T cells, which retain their cytotoxic capacity to eliminate tumor cells, we observed upregulation of ME1 and downregulation of DUSP2 in responders to the combination therapy. However, the mechanistic role of altered ME1 and DUSP2 expression in shaping resilient CD8+ T cell responses in cancer remains to be fully elucidated. To that end, we used scRNA-seq, bulk RNA-seq, and ATAC-seq analyses to investigate how altered expression of DUSP2 and ME1 regulates transcription of genes encoding effector molecules in both human and mouse CD8+ T cells. Additionally, we utilized CD8+ T cell-specific DUSP2 knockout (KO) and ME1 transgenic (Tg) mouse models to define the roles of these genes in effector T cell differentiation and antitumor responses in vivo. We found that DUSP2 downregulation enhances the expression of effector molecules (e.g., GZMB and NKG7) in CD8+ T cells, accompanied by increased cytotoxic activity. Mechanistically, reduced DUSP2 expression promotes chromatin accessibility at effector gene loci by modulating the nuclear residency balance between BAF and NuRD, two chromatin remodeling complexes with opposing functions. In parallel, ME1 overexpression enables activated CD8+ T cells to bypass the classical glycolysis pathway in favor of the pentose phosphate pathway (PPP), thereby boosting ATP production while minimizing excess ROS accumulation and increasing effector molecule expression via an epigenetic mechanism. Our study reveals a previously unknown adaptive mechanism by which resilient CD8+ T cells maintain their cytotoxic function within the TME. This is achieved through integrated reprogramming of epigenetic regulation and metabolic fitness, enabling compensation for metabolic stress in the TME and restoration of responsiveness to ICI-based combination therapy, even in patients with substantial tumor burden. Citation Format: Haidong Dong. Epigenetic and metabolic reprogramming for resilient CD8+ T cell responses in the tumor microenvironment abstract. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A001.
Haidong dong (Wed,) studied this question.